For example, radionuclide studies of the kidney provide a simple noninvasive method of evaluating both total and individual renal function. Radioactively-labeled compounds are utilized for the examinations of patients, for example, to ascertain the shape and function of internal organs and to evaluate the presence and location of pathological processes in the body. For this purpose, a composition comprising the radiopharmaceutical is administered to the patient, for example, in the form of an injectable liquid. By means of suitable detection apparatus, e.g., a gamma camera, images can be obtained of, for example, the organ or the pathological process in which the radioactive compound [radiopharmaceutical] has been incorporated, by recording the emitted radiation.
Compounds which are generally used as radiopharmaceutical agents include inter alia iodine-131 (.sup.131 I), .sup.131 I-orthohippurate (OIH), .sup.125 I-iothalamate, and technetium-99m (.sup.99m Tc) chelates [Eshima et al. (1992) Sem. Nucl. Med. 22: 61-73; Verbruggen, U.S. Pat. No. 4,849,511 (1989); Nosco et al., U.S. Pat. No. 4,925,6501]. To date, one of the most successful agents is considered to be .sup.99m Tc mercaptoacetyltriglycine (.sup.99m TC MAG3). However, although considered to be the renal imaging agent of choice [Cosgriff et al. (1992) Nucl. Med. Comm. 13: 580-585; Verbruggen et al. (1992) J. Nucl. Med. 33: 551-557], .sup.99 Tc MAG3 is still not considered to be an ideal renal imaging agent because there are problems associated with its use. For example, the plasma-protein binding of .sup.99m Tc MAG3 is very high [Taylor et al. (1987) Radiology 162: 365-370; Bubeck et al. (1990) J. Nucl. Med. 31: 1285-1293], the clearance of .sup.99m Tc MAG3 is only 50-60% that of OIH and it does not provide a direct measurement of effective renal plasma flow. Furthermore, a small percentage of .sup.99m Tc MAG3 is transported into the small intestine via the hepatobiliary system in normal volunteers; this percentage increases in patients with renal failure and can lead to problems in image interpretation [Taylor et al. (1987) Contr. Nephrol. 56: 38-46; Taylor et al. (1988) J. Nucl. Med. 29: 616-622; and Dogan et al. (1988) J. Nucl. Med. 29: 616-622]. Increased hepatobiliary activity can also occur with suboptimal kit preparation [Shattuck et al. (1994) J. Nucl. Med. 35: 349-355]. These limitations have prompted a continued need for improved renal imaging agents.
The promising results of .sup.99m Tc MAG3, a triamide mercaptide (N.sub.3 S) compound, led to the synthesis of a number of structural variations of the MAG3 molecule, including replacement of the mercaptoacetyl moiety or one of the three glycines with a variety of natural occurring amino acids. Many of these ligands, labeled with .sup.99m Tc, were tested in mice. The most promising agents were tested in one or two baboons and a few volunteers. In general, these substitutions resulted in products which were inferior to .sup.99m Tc MAG3 or resulted in diastereomers with one diastereomer comparable and the other considerably inferior [e.g., mercaptoacetylglycylalanylglycine (MAGAG) [Verbruggen (1988) J. Nucl. Med. 29: 909]to .sup.99m Tc MAG3. Diastereomeric radiopharmaceuticals with markedly different biokinetics require HPLC purification and are not practical for routine clinical use.
Additional N.sub.3 S ligands were synthesized in order to evaluate the effect of different terminal amino acids and the form of the anionic group on the renal elimination of the compound. .sup.99m Tc mercaptoacetylglycylglycyl-L-alanine (.sup.99m Tc MAG2-Ala), and both complexes of .sup.99m Tc mercaptoacetylglycylglycyl-L-asparagine (.sup.99m Tc MAG2-Asn) and .sup.99m Tc mercaptoacetylglycylglycyl-L-glutamine (.sup.99m Tc MAG2-Gin) were shown to provide promising characteristics as imaging agents [Eshima et al. (1987) J. Nucl. Med. 28: 1180-1186]. Another promising N.sub.3 S type metal chelate, .sup.99m Tc mercaptoacetyl-glycylglycyl-taurine, was found to be inferior to .sup.99m Tc MAG3 in dogs.
It was observed [Verbruggen et al. (1990) In Technetium and rhenium in chemistry and nuclear medicine 3, (Nicolini M., Bandoli G., and Mazzi U. eds) Verona: Cortina International, pp. 445-452] that the polar metabolite, .sup.99m Tc L,L-ethylenedicysteine (.sup.99m Tc LL-EC), of the brain agent, .sup.99m Tc-L,L-ethylenedicysteine diethylester, was rapidly and efficiently excreted into the urine in mice; this observation led to the evaluation of .sup.99m Tc LL-EC as a renal imaging agent. Studies in mice and baboons showed that the pharmacokinetic properties of .sup.99m Tc LL-EC more closely approached those of OIH than the properties of MAG3 and also suggested that LL-EC was superior to the enantiomer .sup.99m Tc DD-EC [Verbruggen et al. (1992) supra; Van Nerom et al. (1990) J. Nucl. Med. 31: 806; Van Nerom et al. (1994) In Radionuclides in nephrology, Blue Bell, Pa.: Field & Wood Medical Periodicals, pp. 13-20].
An ideal, improved .sup.99m Tc complex would be expected to possess a renal clearance that exceeds the clearance of .sup.99m Tc MAG3 by almost 100% in order to approach the clearance of OIH. Such an ideal metal complex could even exceed the clearance of OIH, since the clearance of OIH is only 83% of the clearance of p-aminohippuric acid (PAH), the gold standard for effective renal plasma flow (ERPF) [Bubeck et al. (1990) J. Nucl. Med. 31: 1285-1293]. Not only would a second generation agent provide a better measure of ERPF, the higher clearance would be expected to result in an improved kidney to background ratio and more rapid excretion than MAG3; these features would be expected to result in improved diagnostic studies particularly in neonates, patients with azotemia and patients with suspected obstruction just as the higher clearance of MAG3 compared to DTPA significantly enhanced the diagnostic utility of radionuclide renography in these patient populations.
Thus, there exists a need for a suitable composition for examining renal function comprising a labeled metal chelate which is readily available and easily prepared prior to use, especially in critical circumstances, e.g., in particular for kidney transplantation patients, accident victims and patients after large vascular operations.
There also exists a need for a suitable composition for examining renal function comprising a labeled metal chelate which shows specificity for the organ under examination, e.g., kidney.
There exists a need for a suitable composition for examining renal function, which comprises a labeled metal chelate that does not constitute a serious radiation burden for the patient and that does not have to be administered to the patient only in restricted doses, and which, consequently, does not result in obtaining insufficient information to obtain statistically reliable images of the renal function.
There exists a need for a suitable composition for examining the renal function which comprises a labeled metal chelate that does not present the problem of restricted availability due to too short a half-life and thus precluding the thorough and accurate completion of a renal examination with the metal chelate radionuclide as imaging agent.
There exists a need for a suitable composition for examining the renal function comprising a labeled metal chelate that is capable of being prepared prior to use from a kit formulation in order to maximize the life and stability of the renal imaging composition. The general availability of a ready-to-use labeled product suitable for organ imaging is precluded by the relatively short half-life of radionuclides used in the preparation of imaging agents. Thus, it is desirable to provide an easy and simple procedure for the preparation of a labeled metal chelate just prior to use and conveniently at the place of use. Preferably, it is desirable to provide a kit comprising reaction components necessary for - situ labeling of a ligand precursor, thereby enabling the preparation of a corresponding metal chelate prior to its use as an imaging agent.